Thursday, November 21, 2024 11/21/2024

Identifying pathways required for integration of kidney organoid and host epithelia

Award Number: UC2DK126021
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Kidney disease is the 9th leading cause of death in the U.S. Because few therapies exist to prevent or slow progression, over 700,000 patients have End Stage Renal Disease. These patients are treated with dialysis or renal transplant, the latter resulting in markedly superior survival. However, kidney donors are limited and there is an important unmet need for strategies that enhance renal repair or generate new nephrons for renal replacement. Pluripotent stem cell derived organoids display key features of differentiated kidney tubules and glomerular structures in vitro, and we have shown that they generate patterned nephrons in vivo displaying kidney functions such as filtration and glucose uptake by the proximal tubule. To develop this technology for renal replacement, stem cell derived tubules must be connected to host tubules for urinary output. Our recent work in the zebrafish demonstrated that FGF signaling acts as a chemotactic signal to recruit and polarize cells at sites of new nephron formation and canonical Wnt signaling is required for invasive cell rearrangement to connect tubule lumens. Additional signaling pathways including non-canonical wnt signaling are also likely to play a role in tubule interconnection. To fully explore the requirements for tubule interconnection we have established a synergistic, three-part discovery platform comprising 1) genetic analysis of in vivo new nephron addition in the regenerating zebrafish adult kidney, 2) in vitro 3D cell culture analysis of mammalian epithelial fusion, and 3) in vivo stem cell-derived kidney organoid engraftment to a host mouse collecting system. We will combine these approaches to analyze multiple steps of the tubule fusion process involving 1) recruitment of nephron progenitor cells to target epithelia, 2) removal of intervening ECM/basement membranes, 3) patterned collective cell invasion of target epithelia, and 4) establishment of a continuous patent new lumen to convey the nephron filtrate. These studies will provide important new insights about an essential but understudied cellular mechanism that will be required for in vivo engraftment of new kidney tissue-based renal regeneration therapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $577,585 )
2024	2024	THE MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/21/2024	NON-COMPETING CONTINUATION	$577,585
														Subtotal = $577,585

Issue Date FY: 2023 ( Subtotal = $627,808 )
2023	2023	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/29/2023	NON-COMPETING CONTINUATION	$627,808
2023	2022	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $627,808

Issue Date FY: 2022 ( Subtotal = $627,808 )
2022	2022	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/13/2022	NON-COMPETING CONTINUATION	$627,808
														Subtotal = $627,808

Issue Date FY: 2021 ( Subtotal = $627,808 )
2021	2021	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/11/2021	NON-COMPETING CONTINUATION	$627,808
														Subtotal = $627,808

Issue Date FY: 2020 ( Subtotal = $627,808 )
2020	2020	MOUNT DESERT ISLAND BIOLOGICAL LABORATORY	159 OLD BAR HARBOR RD	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/27/2020	NEW	$627,808
														Subtotal = $627,808

Grand Total All Awards = $3,088,817

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Identifying pathways required for integration of kidney organoid and host epithelia

Award Number: UC2DK126021

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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